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Drug and Alcohol Dependence 51 1998 61᎐71
Genetics of alcohol and other abused drugs
John C. Crabbe
U
, Tamara J. Phillips
Department of Beha
¨
ioral Neuroscience, Portland Alcohol Research Center, Oregon Health Sciences Uni
¨
ersity, VA Medical Center
()
151W , Portland, OR 97201, USA
1. Introduction
Genetic approaches have been applied to the study
of all drugs of abuse with varying degrees of ardor.
Systematic ‘modern’ studies of the genetic influence
on drug sensitivity date at least to the late 1940s,
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when Mardones 1951 demonstrated that rats could
be genetically selected for high or low alcohol
drinking. This basic experiment has been repeated
many times over, with increasing sophistication. A
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systematic and nearly but not completely successful
attempt to review all published studies of genetic
contributions to individual differences in response to
alcohol, barbiturates, opiates, benzodiazepines, co-
caine, amphetamine, nicotine and other drugs through
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early 1991 has been published Crabbe and Harris,
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1991 . Chapters in that volume and many subsequent
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reviews e.g. Smolen and Marks, 1991; Marley et al.,
1992; Crabbe and Li, 1995; Uhl et al., 1995; Mogil et
.
al., 1996; Crawley et al., 1997; Buck et al., 1998
provide basic information about the many genetic
strategies that have been employed for each class of
abused drugs, concentrating on the use of genetic
animal models in preclinical studies. A useful intro-
duction to the methods employed with human popula-
tions to establish genetic influence is provided by
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Crowe 1995 .
This minireview will only briefly describe genetic
methods and their strengths and weaknesses, and will
concentrate on recent findings. The reader will be
referred to relevant reviews for more details about
specific approaches. Also, the review will focus on
genetic influences on drug sensitivity and drug seek-
ing not controlled by differences in bioavailability at
the brain targets of abused drugs. While there are
many human studies implicating genetic predisposi-
U
Corresponding author. Tel.: q1 503 2735298; fax: q1 503
7211029; e-mail: crabbe@ohsu.edu
tion to addiction for specific drugs, and a relatively
new but growing body of work suggesting associations
of particular genes with diagnoses of alcoholism or
drug dependence, the emphasis of this review will be
on research with animal models. Because other pa-
pers in this issue will discuss specific drug classes in
depth, we will concentrate on a few examples for
particular drugs rather than attempt to review current
research exhaustively.
Any abused drug produces multiple responses, of-
ten as a function of dose or chronicity, and several
responses to drugs have been studied using genetic
methods. Individual differences in initial sensitivity,
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the development of tolerance, sensitization ‘reverse
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tolerance’ and dependence as evidenced by the ap-
.
pearance of a withdrawal syndrome are influenced,
but not completely determined, by genes. Also, drugs
have rewarding or punishing effects on behavior, and
both humans and other animals engage in drug-seek-
ing behaviors. It is likely that individual differences in
temperament, emotionality, aggressiveness, neo-
phobia, exploratory drive, and various aspects of
learning capacity and motivation all affect drug re-
sponse magnitude, in both humans and other animals.
All these underlying traits are influenced by genes as
well. Particularly in the area of human genetic predis-
position to abuse drugs, these ‘comorbid’ or con-
founding temperamentrpersonality factors greatly
complicate the effort of researchers to identify speci-
fic domains of genetic risk and delineate their boun-
daries. Genotypes sensitive to one effect of a drug
may sometimes show parallel sensitivity to other ef-
fects. For example, strain sensitivities to nicotine-in-
duced seizures and nicotine oral self-administration
were highly correlated across a panel of inbred mouse
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strains Crawley et al., 1997 . In general, however,
animal studies have shown quite clearly that genetic
predisposition to one effect of a drug does not neces-
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sarily generalize to sensitivity to other effects Crabbe
.
et al., 1994a , nor, sometimes, generalize completely
0376-8716r98r$19.00 ᮊ 1998 Elsevier Science Ireland Ltd. All rights reserved.
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PII S0376-8716 98 00066-0